OBJECTIVES: We have previously reported a top-ranked risk gene [i.e., serine incorporator 2 gene (SERINC2)] for alcohol dependence in individuals of European descent by analyzing the common variants in a genome-wide association study. In the present study, we comprehensively examined the rare variants [minor allele frequency (MAF)<0.05] in the NKAIN1-SERINC2 region to confirm our previous finding. MATERIALS AND METHODS: A discovery sample (1409 European-American patients with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family participants with 1645 alcohol-dependent probands) were subjected to an association analysis. A total of 39,903 individuals from 19 other cohorts with 11 different neuropsychiatric and neurological disorders served as contrast groups. The entire NKAIN1-SERINC2 region was imputed in all cohorts using the same reference panels of genotypes that included rare variants from the whole-genome sequencing data. We stringently cleaned the phenotype and genotype data, and obtained a total of about 220 single-nucleotide polymorphisms in individuals of European descent and about 450 single-nucleotide polymorphisms in the individuals of African descent with 0<MAF<0.05 for an association analysis. RESULTS: Using a weighted regression analysis implemented in the program SCORE-Seq, we found a rare variant constellation across the entire NKAIN1-SERINC2 region that was associated with alcohol dependence in European-Americans (Fp: overall, P=1.8×10(-4); VT: overall, P=1.4×10(-4); Collapsing, P=6.5×10(-5)) and European-Australians (Fp: overall, P=0.028; Collapsing, P=0.025), but not in African-Americans, and not associated with any other disorder examined. Association signals in this region came mainly from SERINC2, a gene that codes for an activity-regulated protein expressed in the brain that incorporates serine into lipids. In addition, 26 individual rare variants were nominally associated with alcohol dependence in European-Americans (P<0.05). The associations of five of these rare variants that lay within SERINC2 showed region-wide significance (P<α=0.0006) and 25 associations survived correction for a false discovery rate (q<0.05). The associations of two rare variants at SERINC2 were replicated in European-Australians (P<0.05). CONCLUSION: We concluded that SERINC2 was a replicable and significant risk gene specific for alcohol dependence in individuals of European descent.
OBJECTIVES: We have previously reported a top-ranked risk gene [i.e., serine incorporator 2 gene (SERINC2)] for alcohol dependence in individuals of European descent by analyzing the common variants in a genome-wide association study. In the present study, we comprehensively examined the rare variants [minor allele frequency (MAF)<0.05] in the NKAIN1-SERINC2 region to confirm our previous finding. MATERIALS AND METHODS: A discovery sample (1409 European-American patients with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family participants with 1645 alcohol-dependent probands) were subjected to an association analysis. A total of 39,903 individuals from 19 other cohorts with 11 different neuropsychiatric and neurological disorders served as contrast groups. The entire NKAIN1-SERINC2 region was imputed in all cohorts using the same reference panels of genotypes that included rare variants from the whole-genome sequencing data. We stringently cleaned the phenotype and genotype data, and obtained a total of about 220 single-nucleotide polymorphisms in individuals of European descent and about 450 single-nucleotide polymorphisms in the individuals of African descent with 0<MAF<0.05 for an association analysis. RESULTS: Using a weighted regression analysis implemented in the program SCORE-Seq, we found a rare variant constellation across the entire NKAIN1-SERINC2 region that was associated with alcohol dependence in European-Americans (Fp: overall, P=1.8×10(-4); VT: overall, P=1.4×10(-4); Collapsing, P=6.5×10(-5)) and European-Australians (Fp: overall, P=0.028; Collapsing, P=0.025), but not in African-Americans, and not associated with any other disorder examined. Association signals in this region came mainly from SERINC2, a gene that codes for an activity-regulated protein expressed in the brain that incorporates serine into lipids. In addition, 26 individual rare variants were nominally associated with alcohol dependence in European-Americans (P<0.05). The associations of five of these rare variants that lay within SERINC2 showed region-wide significance (P<α=0.0006) and 25 associations survived correction for a false discovery rate (q<0.05). The associations of two rare variants at SERINC2 were replicated in European-Australians (P<0.05). CONCLUSION: We concluded that SERINC2 was a replicable and significant risk gene specific for alcohol dependence in individuals of European descent.
Authors: Razia Sultana; Chang-En Yu; Jun Yu; Jeffery Munson; Donghui Chen; Wenhui Hua; Annette Estes; Fanny Cortes; Flora de la Barra; Dongmei Yu; Syed T Haider; Barbara J Trask; Eric D Green; Wendy H Raskind; Christine M Disteche; Ellen Wijsman; Geraldine Dawson; Daniel R Storm; Gerard D Schellenberg; Enrique C Villacres Journal: Genomics Date: 2002-08 Impact factor: 5.736
Authors: Bridget F Grant; Frederick S Stinson; Deborah A Dawson; S Patricia Chou; Mary C Dufour; Wilson Compton; Roger P Pickering; Kenneth Kaplan Journal: Arch Gen Psychiatry Date: 2004-08
Authors: David M Brazel; Yu Jiang; Jordan M Hughey; Valérie Turcot; Xiaowei Zhan; Jian Gong; Chiara Batini; J Dylan Weissenkampen; MengZhen Liu; Daniel R Barnes; Sarah Bertelsen; Yi-Ling Chou; A Mesut Erzurumluoglu; Jessica D Faul; Jeff Haessler; Anke R Hammerschlag; Chris Hsu; Manav Kapoor; Dongbing Lai; Nhung Le; Christiaan A de Leeuw; Anu Loukola; Massimo Mangino; Carl A Melbourne; Giorgio Pistis; Beenish Qaiser; Rebecca Rohde; Yaming Shao; Heather Stringham; Leah Wetherill; Wei Zhao; Arpana Agrawal; Laura Bierut; Chu Chen; Charles B Eaton; Alison Goate; Christopher Haiman; Andrew Heath; William G Iacono; Nicholas G Martin; Tinca J Polderman; Alex Reiner; John Rice; David Schlessinger; H Steven Scholte; Jennifer A Smith; Jean-Claude Tardif; Hilary A Tindle; Andries R van der Leij; Michael Boehnke; Jenny Chang-Claude; Francesco Cucca; Sean P David; Tatiana Foroud; Joanna M M Howson; Sharon L R Kardia; Charles Kooperberg; Markku Laakso; Guillaume Lettre; Pamela Madden; Matt McGue; Kari North; Danielle Posthuma; Timothy Spector; Daniel Stram; Martin D Tobin; David R Weir; Jaakko Kaprio; Gonçalo R Abecasis; Dajiang J Liu; Scott Vrieze Journal: Biol Psychiatry Date: 2018-12-06 Impact factor: 13.382
Authors: Annachiara Rosa; Cinzia Bertelli; Valerie E Pye; Weston B Struwe; Sarah L Maslen; Robin Corey; Idlir Liko; Mark Hassall; Giada Mattiuzzo; Allison Ballandras-Colas; Andrea Nans; Yasuhiro Takeuchi; Phillip J Stansfeld; J Mark Skehel; Carol V Robinson; Massimo Pizzato; Peter Cherepanov Journal: Nat Struct Mol Biol Date: 2020-01-06 Impact factor: 15.369